A number of analogs of cyclic AMP have been found to cause the death of cultured H35 rat hepatoma cells. Among these are two 6-Thio derivatives; 6-HScRMP and 6-MeScRMP and two 8-amino derivatives; 8-H2NcAMP and 8-OHEtHNcAMP. These compounds cause rapid cell death in the micromolar concentration range. A major effort in the proposed studies will be to select cells resistant to the lethal action of each of the four analogs. Determination of cross-resistance to the other analogs should help analysis of the mechanism by which these analogs act. Analogs will also be added during various phases of the cell cycle in synchronized cells to determine whether or not they exert their effects on a specific cell cycle process (e.g., DNA replication). The ability of these analogs to inhibit RNA, DNA and protein synthesis will also be assessed with appropriate corrections made for possible inhibition of precursor uptake. Efforts will be made to determine whether any of these compounds are incorporated into RNA or DNA. Finally, the degree to which these analogs are subject to hydrolysis by the phosphodiesterase in H35 cells will be determined in broken cell preparations plus or minus inhibitors of phosphodiesterase.